We have previously described certain polyurethane materials and methods for forming an implant in situ, as described, for example, in US patents and publications U.S. Pat. Nos. 6,254,327, 6,296,607, 6,702,731, 7,044,982, 7,047,980, 2002-0049503, 2002-0049363, 2003-0135238, 2003-0194505, 2003-0188755, 2004-0068078, 2003-0135238, 2005-0129733, 2005-0070913, 2005-0187429, 2005-0215748, 2005-0247322 and 2006-01198816, each of which is incorporated herein by reference. The materials used are a small subset of the large number of polyurethane materials. Examples of polyurethane materials that are similar but are not believed to be suitable for implantation in the body include those described by U.S. Pat. Nos. 3,380,967; 3,607,822; 5,338,767; 6,255,433; and 2004/0076758. U.S. Pat. No. 3,923,926 to Kuroda et al describes a material formally similar to our preferred ranges, but which produce dissimilar results. U.S. Pat. Nos. 5,173,301, 4,994,542, 4,806,614, 4,740,534, and 5,173,301, to Matsuda and colleagues, describe polymerization of urethanes in situ in the body.
There are numerous medical conditions in which filling a space, or adding bulk to a tissue, is needed to alleviate the condition Tissue bulking is believed to be helpful in tightening sphincters, for example in the esophagus and bladder. U.S. Pat. No. 5,785,642 (Wallace et al.) describes a 3-part injectable polymer for treating incontinence. The patent claims improved resistance to migration, principally when compared with particulate injectables. The invention in 5,785,642 involves forming a polymer precipitate in situ from a solvent/polymer system. Since the solvent does not entirely become part of the precipitate, some of the injected solvent volume is eventually lost to absorption into the surrounding tissue. Thus, Wallace does not teach a device which has a stable volume once implanted.
U.S. Pat. No. 5,712,252 (Smith) describes a method of augmenting soft tissue in a mammal which includes injecting keratin into soft tissue. Keratin is a biodegradable substance. U.S. Pat. No. 5,763,399 (Lee) describes a composition and method for effective revitalization of scar tissue by injecting a bioactive substance having angiogenic activity. The revitalization of scar tissue is intended to augment existing tissue. However, this invention cannot control the extent of augmentation.
U.S. Pat. No. 5,922,025 (Hubbard) describes a permanent, biocompatible material for soft tissue augmentation. The biocompatible material comprises a matrix of smooth, round, finely divided, substantially spherical particles of a biocompatible ceramic material. However, prevention of migration of the ceramic material is not described. U.S. Pat. No. 5,976,526 (Atala) describes treatment of vesicoureteral reflux, incontinence and other defects using an injectable preparation of bladder cells mixed with a liquid polymeric material. This material is susceptible to biodegradation. U.S. Pat. No. 5,855,615 (Bley at al) describes a composition for injecting into the urethra comprising a plurality of physiologically acceptable solid polymer particles dispersed in a physiologically acceptable bio-dissipatable liquid carrier. The solid polymer particles are capable of hydrating to a predetermined volume. The injection volume is therefore not necessarily the same as the final hydrated volume. U.S. Pat. No. 5,709,854 (Griffith-Cima et al) describes a cell polymeric solution that self-crosslinks for the purpose of inducing tissue formation.
One of the uses of the present invention is treatment of urinary incontinence. In particular, many women suffer from incontinence caused by childbirth or obesity. The initial treatment for stress incontinence is exercise to strengthen the pelvic floor muscles. If these exercises are ineffective, open surgical repair of the bladder neck is often attempted. Such surgical repair procedures are not successful for all patients. There is also risk associated with open surgical procedures, such as trauma, infection, and risks of anesthesia.
As an alternative to surgical repair, urinary incontinence has been treated by injecting various substances into the tissue surrounding the urethra, i.e., the periurethral tissue, to add bulk to this tissue. The aim of this treatment is to compress the urethra at the level of the bladder neck to impede involuntary flow of urine from the bladder. Murless has reported the use of sodium morrhuate for the treatment of stress incontinence (Murless, “The Injection Treatment of Stress Incontinence,” J. Obstet. Gynaecol., 45:67-73 (1938).) This material was not successful in treating incontinence and pulmonary infarction was an observed complication. Paraffin and other sclerosing solutions have been tried, yielding poor results (Quackels, “Deux Incontinences Apres Adenomecomie Gueries Par Injection de Paraffine Dans Le Perince,” “Acta Urol. Belg., 23:259-262 (1955); Sachse, “Treatment of Urinary Incontinence with Sclerosing Solutions: Indications, Results, Complications,” Urol. Int., 15:225-244 (1963)).
Polytetrafluoroethylene (PTFE) particles (TEFLON™, POLYTEF™) have been used as injectable bulking material with a success rate from 30% to 86% in some studies (e.g., Politano, et al., “Periurethral Teflon Injection for Urinary Incontinence,” J. Urol., 111:180-183 (1974); Lim, et al., “Periurethral Teflon Injection: A Simple Treatment for Urinary Incontinence,” Br. J. Urol, 55:208-210 (1983); Schulman, et al., “Endoscopic Injection of Teflon to Treat Urinary Incontinence in Women,” BMJ, 228:192 (1984); Rodriguez, “Late Results of the Endouretbral Injection of Teflon in Stress Urinary Incontinence,” J. Urol. (Paris), 62:39-41 (1987); Vesey, et al., “Teflon Injection in Female Stress Incontinence. Effect on Urethral Pressure Profile and Flow Rate,” Br. J. Urol., 62:39-41 (1988); Smart, “Poltef Paste for Urinary Incontinence,” Aust. N. Z. J. Surg., 61:663-666 (1991).) The complications associated with PTFE injection have included foreign body granulomas which tended to migrate to distant organs, such as the lungs, liver, spleen and brain (Malizia, et al., “Migration and Granulomatous Reaction After Periurethral Injection of Polytef (Teflon),” JAMA, 251:3227-3281 (1984)).
Another injectable that has been used is glutaraldehyde cross-linked bovine dermal collagen (Stricker, et al., “Injectable Collagen for Type 3 Female Stress Incontinence: The first 50 Australian Patients,” Med. J. Aust., 158:89-91 (1993); Capozza, et al., “Endoscopic Treatment of Vesico-Ureteric Reflux and Urinary Incontinence: Technical Problems in the Pediatric Patient,” Br. J. Urol., 75:538-542 (1995).) A major problem with the use of collagen was biodegradation with associated decrease in implant volume over time necessitating retreatment. Collagen can also cause adverse immune responses and allergic reactions to bovine collagen have been described (Moore, et al., “Periurethral implantation of Glutaraldehyde CrossLinked Collagen (Contigen®) in Women with Type I or III Stress Incontinence: Quantitative Outcome Measures,” Br. J. Urol., 75:359-363 (1995)).
Other materials have been suggested for use in the treatment of vesicourectal reflux. These substances include polyvinyl alcohol foam (Meriguerian, et al., “Submucosal Injection of Polyvinyl Alcohol Foam in Rabbit Bladder,” J. Urol., 144:531-533 (1990)), glass particles (Walker, et al., “Injectable Bioglass as a Potential Substitute for Injectable Polytetrafluoroethylene,” J. Urol, 148:645 (1992)), a chondrocyte-alginate suspension (Atala, et al., “Injectable Alginate Seeded with Chondrocytes as a Potential Treatment for Vesicoureteral Reflux,” J. Urol., 150:745-747 (1993)) and a detachable silicone balloon (Atala, et al., “Endoscopic Treatment of Vesicoureteral Reflux with a Self-Detachable Balloon System,” J. Urol., 148:724-728 (1992)).
Small poly-like nodules in the gastroesophageal tract can be removed by a procedure known as endoscopic mucosal resection (EMR). The nodule is first injected at its base with a solution that will decrease bleeding after the nodule is removed. The resulting bleb under the nodule raises the tissue and separates tissue layers, and thereby enables the doctor to remove it without damaging the rest of the esophagus or bowel. The EMR is done using a small cap that has a small wire loop which fits on the end of the endoscope. The nodule is suctioned into the cap and the wire loop is closed while cautery is applied. This is done so that the tissue can be examined under a microscope to determine if all of the cancer (or dysplasia) has been removed. If the cancer is not completely removed, additional visits may be needed to completely remove the cancer. When the nodule is completely removed, additional treatment can be done, such as photodynamic therapy if the nodule was cancerous.
Currently, this resection of the mucosal layer is done using a solution of saline to lift the mucosal layer so the polyp or nodule can be removed. One difficulty in the use of the saline is that it dissipates rapidly. The procedure can be much improved if a more viscous injectable were used. Preferably, the injectable would not migrate, and more preferably, it would act as a gel or solid once placed, to cap and protect the site after nodule removal.
Another example of space filling is treatment of the spinal disk. The spinal intervertebral disk comprises a fibrous support structure, the annulus fibrosis (“annulus”), a resilient structure connecting adjacent vertebrae, and the nucleus pulposus (“nucleus”), a gelatinous substance normally enclosed in a space formed by the annulus and the end plates of the vertebrae. Herniation of the disk involves partial failure of the annulus, and may allow part of the nucleus to protrude from the center of the disk. A contained disk herniation is one that is not associated with free nucleus fragments migrating to the spinal canal. However, even a contained disk herniation can still protrude and irritate surrounding structures, for example by applying pressure to spinal nerves. Escaped nucleus can chemically irritate neural structures.
Current treatment methods include reduction of pressure on the annulus by removing some of the interior nucleus pulposus material by percutaneous nucleotomy. See, for example, Kambin U.S. Pat. No. 4,573,448. Complications of nucleotomy include disk space infection, nerve root injury, hematoma formation, instability of the adjacent vertebrae and collapse of the disk from decrease in height. It has been proposed to treat weakening due to nucleus pulposus deficiency by inserting preformed hydrogel implants. See, Ray U.S. Pat. Nos. 4,772,287; 4,904,260 and, 5,562,736 and Bao U.S. Pat. No. 5,192,326.
Circumferential bulging of the spinal disk also can result in chronic disk weakening. The joint can become mechanically less stable. As the bulging disk extends beyond its normal circumference, the disk height is compromised and nerve roots are compressed. In some cases osteophytes form on the outer surface of the disk and further encroach on the spinal canal and channels through which nerves pass. This condition is known as lumbar spondylosis. Continued disk degeneration can result in one vertebral body segment approaching and possibly contacting an adjacent vertebral body segment.
Delivery of tissue adhesives to the spine in a minimally invasive manner has been disclosed, and includes procedures for restoring structural integrity to vertebral bodies. See Scribner U.S. Pat. Nos. 6,241,734 and 6,280,456; Reiley U.S. Pat. Nos. 6,248,110 and 6,235,043; Boucher U.S. Pat. Nos. 6,607,554 and Bhatnagar et al 6,395,007. Methods of repairing the spinal disk or portions thereof are disclosed in Cauthern U.S. Pat. No. 6,592,625, Haldimann U.S. Pat. No. 6,428,576, Trieu U.S. Pat. No. 6,620,196 and Milner et al U.S. Pat. No. 6,187,048.
Delivery of a liquid or low modulus prosthetic to the nuclear space requires constructing a passageway into the nucleus and removal of the nucleus, in total or in part. The passageway is usually made through the annulus, especially when part of the annulus must be removed to correct a pathological condition. Whether the passageway is through the annulus or elsewhere, for example, through the vertebral body, there is a risk of the nucleus prosthetic extruding through the passageway. Nucleus prosthetic extrusion can affect the surrounding nerves adversely. Methods of blocking a passageway made through the annulus are disclosed in Lambrecht U.S. Pat. No. 6,425,919, Lambrecht, et al. U.S. Pat. Nos. 6,482,235, 6,508,839, 6,821,276 and 6,883,520, and Cauthen U.S. Pat. No. 6,592,625. Other methods of preventing nucleus prosthetic extrusion include enclosing the prosthetic entirely inside of an enveloping sheath and are disclosed in Ray, et al. U.S. Pat. No. 4,904,260, Bao, et al. U.S. Pat. No. 5,192,326, Kuslich U.S. Pat. No. 5,549,679, Stalcup, et al. U.S. Pat. No. 6,332,894, Wardlaw U.S. Pat. No. 6,402,784, Weber, et al. U.S. Pat. No. 6,533,818, and Reuter, et al. U.S. Pat. No. 6,805,715. Still other methods of preventing nuclear prosthetic extrusion include delivering a preformed prosthetic in a reduced state, which when introduced into the body increases in volume. These methods and devices are disclosed in Ray et al. U.S. Pat. No. 6,602,291, Stoy et al. U.S. Pat. No. 6,726,721, and Li et al. U.S. Pat. No. 6,764,514.
Many other opportunities are available for the use of a space-filling material in medicine and surgery. Spaces that could be filled include the spaces left by lumpectomies and similar procedures, especially in the breast. Bulking can correct cosmetic defects, especially those due to aging; and bulking may have more demanding applications, such as bulking heart valves. Other uses in the body include vocal chord augmentation, filling wrinkles, treatment of gastroesophageal reflux, and replacement of the aqueous portion of the eye.
However, all of these applications require implantable materials, and as seen in the review above, there are problems with many of the materials being tested for these purposes, and there are few solutions actually in use in medical practice. Hence, there is an ongoing need for improved materials for these and other uses.